11-β-hydroxy steroid dehydrogenase type 1 (11β-hydroxy steroid dehydrogenase 1) glucocorticoid (cortisol in human, corticosterone in rodent) is a counter-regulatory hormone, which resists against the action of insulin (Dallman M F, Strack A M, Akana S F et al., 1993; Front Neuroendocrinol 14, 303-347). This controls the expression of hepatic enzymes related to gluconeogenesis, and increases substrate supply by releasing amino acid (decrease of protein synthesis and increase of proteolysis) from muscle, and glycerol (increase of lipolysis) from adipose tissue. Glucocorticoid is also important in differentiation of preadipocytes into mature adipocytes capable of storing triglyceride (Bujalska I J et al., 1999; Endocrinology 140, 3188-3196). This may be critical in disease states where glucocorticoid induced by “stress” is related to central obesity which itself is a strong risk factor of type 2 diabetes mellitus, hypertension and cardiovascular disease (Bjorntorp P and Rosmond R, 2000; Int. J. Obesity 24, S80-S85).
Activity of glucocorticoid is controlled not only by secretion of cortisol but also at the tissue level by intracellular interconversion of inactive cortisone and active cortisol by 11-β hydroxy steroid dehydrogenase, 11βHSD1 (activating cortisone) and 11βHSD2 (inactivating cortisol) (Sandeep T C and Walker B R, 2001 Trends in Endocrinol & Metab. 12, 446-453). Isoform 11-β hydroxy steroid dehydrogenase type 1 (11βHSD1) is expressed in liver, adipose tissue, brain, lung and other glucocorticoid tissues, and is a potential target for treating a number of diseases (such as diabetes mellitus, obesity and age-related cognitive disorder) that can be improved by a reduction of action of glucocorticoid (Seckl et al. 2001; Endocrinology 142, 1371-1376).
The role of 11βHSD1, as an important regulatory system in local glucocorticoid efficacy, and thus production of hepatic glucose have proved (Jamieson et al. 2000; J. Endocrinol, 165, 685-692). The fact that an intracellular interconversion mechanism of inactive cortisone and active cortisol may be important in humans was initially shown by treatment with carbenoxolone (antiulcerative drug inhibiting both 11βHSD1 and 2) (Walker B R et al., 1995; J. Clin. Endocrinol. Metab. 80, 3155-3159). This leads to increased insulin sensitivity indicating that 11βHSD1 may control the effects of insulin by reducing tissue levels of active glucocorticoids (Walker B R et al, 1995; J. Clin. Endocrinol. Metab. 80, 3155-3159). Also, studies on compounds having a therapeutic effect on type 2 diabetes mellitus by inhibition of 11βHSD1 have been recently actively conducted (Ji Seon Part et al., biological pharmacology, Anti-diabetic and anti-adipogenic effects of a novel selective 11βhydroxysteroid dehydrogenase type 1 inhibitor, 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR-66344), 2011; Sundbom M et al., Inhibition of 11beta HSD1 with the S-phenylethylaminothiazolone BVT116429 increases adiponectin concentrations and improves glucose homeostasis in diabetic KKAy mice, BMC Pharmacology 2008; 8:3 (12 Feb. 2008); Clarence Hale et al., Chem Bio/Drug Des 2008; 71:36-44; Clarence Hale et al., Diabetes, Obesity and Metabolism 11: 2009, 109-117; G. Hollis R. Huber, 2010; Diabetes, Obesity and Metabolism 13: 1-6, 2011: Clarence Hale et al., J. Med. Chem. 2010, 53, 4481-4487)
Clinically, Cushing's syndrome is related to an excess of cortisol, which is associated with glucose tolerance, central obesity (caused by simulation of preadipocyte differentiation in this depot), dyslipidemia and hypertension. Cushing s syndrome clearly shows a number of similarities to metabolic syndrome. Although the metabolic syndrome is not generally related to excess circulating cortisol levels (Jessop D S et al., 2001; J. Clin. Endocrinol. Metab. 86, 4109-4114), abnormally high 11βHSD1 activity within tissues would be expected to have the same effect. In a case of an obese person, although he has a plasma cortisol level lower than or similar to a lean control, the 11βHSD1 activity in his subcutaneous fat was highly increased (Rask E, et al. 2001; J. Clin. Endocrinol. Metab. 1418-1421). Also, the central fat related to the metabolic syndrome shows a much higher 11βHSD1 activity than subcutaneous fat (Bujalska I J et al., 1997; Lancet 349, 1210-1213). Accordingly, it is thought that glucocorticoid, 11βHSD1 and metabolic syndrome have relations therebetween.
11βHSD1 knockout mice show attenuated glucocorticoid-induced activation of gluconeogenesis enzymes in response to plasma glucose levels lacking or reduced in response to stress or obesity (Kotelevtsev Y et al., 1997; Proc. Natl. Acad. Sci USA 94, 14924-14929). This indicates that inhibition of 11βHSD1 is useful in reduction of plasma glucose and hepatic glucose output in type 2 diabetes mellitus. Also, these mice express an anti-arteriosclerotic lipoprotein profile that shows a low triglyceride level, an increase of HDL cholesterol and an increase of apo-lipoprotein AI level (Morton N M et al., 2001; J. Biol. Chem. 276, 41293-41300). Such a phenotype is caused by an increase of hepatic expression of enzymes of fat catabolism and PPARα. Also, this indicates that 11βHSD1 inhibition is useful in treatment of dyslipidemia of the metabolic syndrome.
The most reliable demonstration of a relation between metabolic syndrome and 11βHSD1 was obtained from a recent study on transgenic mice over-expressing 11βHSD1 (Masuzaki H et al., 2001; Science 294, 2166-2170). When 11βHSD1 is expressed under the control of an adipocyte specific promoter, 11βHSD1 transgenic mice show high adipose levels of corticosterone, central obesity, insulin resistant diabetes mellitus, hyperlipidemia and bulimia nervosa. Most importantly, an increase levels of 11βHSD1 in the fat of these mice are similar to those observed in diabetes mellitus individuals. Fat 11βHSD1 activity and plasma corticosterone levels were normal, but hepatic portal vein levels of corticosterone were increased three times. This is thought to be a cause of themetabolic effects in liver.
It is clear that a mouse can completely imitate metabolic syndrome by over-expressing 11βHSD1 only in fat to a similar level as that of an obese human.
Tissue distribution of 11βHSD1 is widely spread, and overlaps with that of glucocorticoid receptor. Accordingly, inhibition of 11βHSD1 may potentially oppose the effects of glucocorticoid in a large number of physiological/pathological roles. It is widely disclosed that 11βHSD1 is present in human skeletal muscle and glucocorticoid opposes insulin's anabolic effects on protein turnover and glucose metabolism (Whorwood C B et al., 2001; J. Clin. Endocrinol. Metab. 86, 2296-2308). Accordingly, skeletal muscle may be an important target for 11βHSD1-based treatment.
Glucocorticoid can also reduce insulin secretion and worsen the effects of glucocorticoid induced insulin resistance. Pancreatic islets express 11βHSD1, and carbenoxolone can inhibit the effects of 11-dehydro corticosterone on insulin release (Davani B et al., 2000; J. Biol. Chem. 275, 34841-34844). Accordingly, in treatment of diabetes mellitus, 11βHSD1 inhibitor may not only act at the tissue level on insulin resistance but also increase insulin secretion itself.
Skeletal development and bone function are also regulated by glucocorticoid action. 11βHSD1 is present in human bone osteoclasts and osteoblasts, and treatment of healthy volunteers with carbenoxolone showed a decrease in bone resorption with no change in bone formation markers (Cooper M S, et al. 2000; Bone 27, 375-381). Inhibition of 11βHSD1 activity in bone could be used as a protection mechanism in treatment of osteoporosis.
Glucocorticoid may also be involved in ocular disease such as glaucoma. 11βHSD1 has been shown to affect intraocular pressure in humans and inhibition of 11βHSD1 may be expected to alleviate an increase of intraocular pressure associated with glaucoma (Rauz S et al., 2001; Investigative Opthalmology & Visual Science 42, 2037-2042).
It is known that stress and glucocorticoid affect a cognitive function (de Quervain et al., 1998; Nature 394, 787-790). 11βHSD1 controls the level of the glucocorticoid action in the brain and thus is helpful in neurotoxicity (Rajan, V. et al., 1996; Neuroscience 16, 65-70; Seckl et al., 2000; Neuroendocrinol, 18, 49-99). Based on the known efficacy of gluticorticoid in the brain, inhibition of 11βHSD1 in the brain may result in reduced anxiety (Tronche, F. et al., 1999; Nature Genetics, 23, 99-103). Inhibition of 11βHSD1 in a human brain may prevent reactivation of cortisone into cortisol, and protect against harmful glucocorticoid-mediated effects on neuronal survival and other aspects of neuronal function, including cognitive disorder, depression and increase of appetite.
There appears to be a certain relation between 11βHSD1 and metabolic syndrome both in humans and rodents. A drug that specifically inhibits 11βHSD1 in type 2 obese diabetic patients will lower blood sugar by inhibiting hepatic gluconeogenesis, reduce central obesity, improve the atherogenic lipoprotein phenotype, lower blood pressure, and reduce insulin resistance. Insulin effects in muscle will be enhanced, and insulin secretion from beta cells of Pancreatic islets may also be increased.
At present, there are two main recognized definitions of metabolic syndrome.
1) The adult treatment panel (ATP III 2001 JMA) definition of metabolic syndrome indicates that it is present if the patient has three or more of the following symptoms:                waist measurements of 40 inches (102 cm) or more for men, and 35 inches (88 cm) or more for women        serum triglyceride level of 150 mg/dl (1.69 mmol/1) or more        HDL cholesterol levels of less than 40 mg/dl (1.04 mmol/1) for men, and less than 50 mg/dl (1.29 mmol/1) for women        blood pressure of 135/80 mm Hg or more and/or        blood sugar (serum glucose) of 110 mg/dl (6.1 mmol/1) or more.        
2) The WHO advisory committee has recommended the following definition which does not imply causal relationships and is suggested as a working definition to be improved upon in due course:                The patient has at least one of the following symptoms: glucose tolerance, impaired glucose tolerance (IGT) or diabetes mellitus and/or insulin resistance together with two or more of the following:        raised arterial pressure        raised plasma triglycerides        central obesity        microalbuminuria.        
Accordingly, The present invention provides a novel compound and a pharmaceutical composition including the same for inhibiting human 11-β-hydroxy steroid dehydrogenase type 1, which are more excellent in activity and solubility, and is more efficient in formulation and transfer.